1. Field of the Invention
The present invention provides LH-RH receptor antagonists containing cyclic pentapeptides or salts thereof having an LH-RH receptor antagonistic effect and novel cyclic pentapeptides or salts thereof having an excellent LH-RH receptor antagonistic effect.
2. Description of Related Art
The secretion of anterior pituitary hormones is controlled by peripheral hormones to be secreted by the organs, which are targeted by the individual anterior pituitary hormones, and also by secretion-promoting or secretion-retarding hormones to be secreted by the hypothalamus which is the upper center of the anterior lobe of hypophysis (these hormones are hereinafter referred to as hypothalamus hormones). At present, the presence of nine hypothalamus hormones has been confirmed, which include, for example, thyrotropin releasing hormone (TRH) and gonadotropin releasing hormone (GnRH) [this is also referred to as luteinizing hormone releasing hormone (LH-RH)] (Irie, M. & Toyama, K., Physiology 2, Bunkodo Publishing, pp. 610-618, 1986). It is presumed that these hypothalamus hormones exhibit their hormone effects, etc. via the receptors which are considered to exist in the anterior lobe of hypophysis (ibid.), and the analysis of receptor genes specific to these, including those of human beings, is being promoted (Imura, H. et al.; Bases and Clinics of Receptors, Asakura Shoten Publishing, pp. 297-304, 1993). Therefore, antagonists and agonists which are specific and selective to these receptors shall control the action of hypothalamus hormones and control the secretion of anterior pituitary hormones. As a result, such antagonists and agonists are expected to be useful for prevention and curing of disorders dependent on such anterior pituitary hormones.
The repeated administration of leuprorelin acetate, a highly-active derivative of luteinizing hormone releasing hormone (hereinafter referred to as LH-RH) which is one of hypothalamus hormones (Fujino et al., Biochemical and Biophysical Research Communication, Vol. 60, pp. 406-413, 1975; Oliver, R. T. D., et al., Br. J. Cancer, Vol. 59, p. 823, 1989; and Toguchi, et al., J. Int. Med. Res., Vol. 18, pp. 35-41, 1990) lowers the release and production of luteinizing hormone at hypophysis, lowers the reactivity of testis and ovarium on luteinizing hormone and retards the secretion of testosterone and estrogen. Accordingly, it is known that leuprorelin acetate exhibits anti-tumoral activity against cancers dependent on such hormones, such as prostatic cancer, and it has been applied to clinical use. In addition, leuprorelin acetate has been widely applied to clinical use as a medicine for curing endometriosis, puberty precox, etc. It is presumed that the high carcinostatic activity of leuprorelin acetate will result from the fact that it is more resistant to proteases than natural LH-RH and the fact that it has high affinity with LH-RH receptors thereby causing the desensitization of the reactivity of LH-RH due to the decrease in the number of its receptors. However, since leuprorelin acetate is an super-agonist for LH-RH receptors, it is reported that the acetate causes transient exacerbation that is accompanied by the increase in the serum testosterone concentration, due to its pituitary-gonadotropic effect (acute effect), immediately after the first administration thereof.
Given the background situations as above, LH-RH antagonists are desired which have more excellent curing effect while not exhibiting the above-mentioned transient pituitary-gonadotropic effect (acute effect).
The various cyclic pentapeptides (FEBS LETTERS, vol. 291, No. 1, 50-54 (1991), Biochemical Society Transactions, Current Techniques in Polypeptide Structure and Synthesis, 1049-1052 (1994), U.S. Pat. No. 4,508,711, EP-A 436,189, EP-A 528,312, EP-A 606881, Japanese Patent Laid-Open No. 3-94692, 3-130299, 6-192293, 5-59098 and 5-194589) have been reported. However, they have not disclosed about LH-RH receptor antagonistic effect.
As compounds showing LH-RH antagonistic effect, linear peptides (U.S. Pat. Nos. 5,140,009 and 5,171,835), cyclic hexapeptide derivatives (Japanese Patent Laid-Open No. 61-191698, EP-A 0190946), bicyclic peptide derivatives (Journal of Medicinal Chemistry, Vol. 36, pp. 3265-3273, 1993), etc have been reported.